US2025002490A1PendingUtilityA1
Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof
Assignee: SHENZHEN HIGHTIDE BIOPHARMACEUTICAL LTDPriority: Jul 29, 2014Filed: Apr 9, 2024Published: Jan 2, 2025
Est. expiryJul 29, 2034(~8 yrs left)· nominal 20-yr term from priority
Inventors:Liping Liu
C07J 63/008A61K 31/194A61K 31/19A61K 31/357A61K 31/202C07J 41/0061C07J 41/0055C07J 43/003C07J 31/006C07J 9/005C07D 471/14C07D 455/03A61K 31/4745A61K 31/4375
66
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Claims
Abstract
The invention provides various novel compositions of berberine in combination with pharmacologically active organic acids, and related methods of their use in treating various diseases or disorders. The invention further provides various novel compounds prepared from berberine and pharmacologically active organic acids and prepared from ursodeoxycholic acid and pharmacologically active organic bases, and pharmaceutical compositions thereof, and methods of their preparation and therapeutic use in treating and/or preventing various diseases or disorders. The compounds and pharmaceutical compositions of the invention can be utilized to treat various diseases or disorders, such as diabetes, diabetic complications, dyslipidemia, hyperlipidemia, obesity, metabolic syndromes, pre-diabetes, atherosclerosis, heart diseases, neurodegenerative diseases, sarcopenia, muscle atrophy, inflammation, cancer and liver diseases and conditions such as fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cholestatic liver diseases or graft-versus-host disease of the liver. The compounds of this invention are also useful in improving liver functions in chronic viral associated liver diseases and alcohol-related liver diseases.
Claims
exact text as granted — not AI-modifiedWhat is Claimed is:
1 . A composition comprising:
(a) berberine or a derivative or analog thereof; (b) one or more pharmacologically active organic acids; and (c) optionally a pharmaceutically acceptable excipient, carrier, or diluent, wherein the berberine and the pharmacologically active organic acid are present in amounts that, when administered to a subject, are sufficient to treat, prevent, or reduce one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, neurodegenerative diseases, liver diseases, sarcopenia, muscle atrophy, inflammation, and cancer, or a related disease or disorder thereof in a mammal, including a human.
2 . The composition of claim 1 , wherein the one or more pharmacologically active organic acids are selected from the group consisting of ┐-(+)-α-lipoic acid, hydroxycitric acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, ursolic acid, corosolic acid cholic acid, obeticholic acid, ursodeoxycholic acid, and organic acid selected from Table 1.
3 . The composition of claim 1 or 2 , wherein the composition comprises a berberine derivative or analog selected from Table 2.
4 . The composition of any of claims 1-3 , further comprising a third agent selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium
5 . The composition of any of claims 1-4 , wherein the disease or disorder is a metabolic disorder is selected from diabetes, diabetic complications, obesity, dyslipidemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, metabolic syndromes, pre-diabetes, fatty liver, NAFLD and NASH.
6 . The composition of any of claim 5 , wherein the metabolic disorder is type 1 or type 2 diabetes.
7 . The composition of any of claim 5 , wherein the diabetic complications is diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or macrovascular complications comprising heart attacks, strokes or insufficiency in blood flow to legs.
8 . The composition of any of claims 1-4 , wherein the disease or disorder is heart diseases or atherosclerosis.
9 . The composition of any of claims 1-4 , wherein the disease or disorder is neurodegenerative diseases.
10 . The composition of any of claims 1-4 , wherein the disease or disorder is cancer.
11 . The composition of claim 10 , wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, lung cancer, hepatocellular carcinoma, pancreatic cancer, gastric carcinoma, colorectal cancer, leukemia, multiple myeloma, melanoma and glioblastoma.
12 . The composition of any of claims 1-4 , wherein the disease or disorder is sarcopenia or muscle atrophy.
13 . The composition of claim 12 , wherein the disease or disorder is skeletal muscle atrophy.
14 . The composition of claim 1 , comprising a pharmaceutically acceptable excipient, carrier, or diluent.
15 . The composition of claim 1 , comprising berberine and ┐-(+)-┐-Lipoic acid, berberine and hydroxycitric acid, berberine and one or both of EPA and DHA, berberine and one or both of ursolic acid and corosolic acid, or berberine and one or both of cholic acid and ursodeoxycholic acid.
16 . The composition of claim 15 , further comprising an agent selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium.
17 . A method for treating, reducing, or preventing a metabolic disorder, heart diseases, neurodegenerative diseases, liver diseases comprising
administering to a subject in need thereof a pharmaceutical composition comprising
(a) berberine or a derivative or analog thereof; and
(b) one or more pharmacologically active organic acids, in a therapeutically effective amount, and
(c) optionally a pharmaceutically acceptable excipient, carrier, or diluent.
18 . The method of claim 17 , wherein the metabolic disorder is selected from diabetes, diabetic complications, obesity, dyslipidemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, metabolic syndromes, pre-diabetes, fatty liver, NAFLD and NASH.
19 . The method of claim 17 or 18 , wherein the metabolic disorder is type 1 or type 2 diabetes.
20 . The method of claim 17 or 18 , wherein the metabolic disorder is dyslipidemia, or diabetic dyslipidemia, or dyslipidemia in statin-intolerant patients.
21 . The method of claim 17 or 18 , wherein the metabolic disorder is fatty liver, or NAFLD.
22 . The method of claim 17 or 18 , wherein the metabolic disorder is NASH.
23 . The method of claim 17 or 18 , wherein the diabetic complications are diabetic neuropathy, diabetic retinopathy, diabetic nephropathy or macrovascular complications comprising heart attacks, strokes or insufficiency in blood flow to legs.
24 . The method of claim 17 or 18 , wherein the pre-diabetes is impaired fasting glycaemia and/or impaired glucose tolerance.
25 . The method of any of claims 17-24 , wherein the one or more pharmacologically active organic acids is selected from the group consisting of ┐-(+)-α-lipoic acid, hydroxycitric acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, ursolic acid, corosolic acid, cholic acid, obeticholic acid, ursodeoxycholic acid, or the others listed in Table 1.
26 . The method of any of claims 17-25 , wherein the pharmaceutical composition comprises a berberine derivative or analog selected from Table 2.
27 . The method of any of claims 17-26 , wherein the pharmaceutical composition further comprises one or more agent selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium.
28 . The method of claim 17 , wherein
the pharmaceutical composition comprises berberine and ┐-(+)-α-lipoic acid, and the subject suffers from diabetes and/or diabetic complications.
29 . The method of claim 17 , wherein
the pharmaceutical composition comprises berberine and hydroxycitric acid, and the subject suffers from diabetes and/or obesity.
30 . The method of claim 17 , wherein
the pharmaceutical composition comprises berberine and one or both of EPA and DHA, and the subject suffers from diabetes and/or dyslipidemia, heart diseases, atherosclerosis, or neurodegenerative diseases.
31 . The method of claim 17 , wherein
the pharmaceutical composition comprises berberine and one or both of ursolic acid and corosolic acid, and the subject suffers from diabetes and sarcopenia, or muscle atrophy.
32 . The method of claim 17 , wherein
the pharmaceutical composition comprises berberine and one or more of cholic acid, obeticholic acid and ursodeoxycholic acid, and the subject suffers from dyslipidemia, diabetic dyslipidemia, fatty liver, NAFLD, or NASH.
33 . The method of any of claims 28-32 , wherein the pharmaceutical composition further comprises one or more agents selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium.
34 . The method of any of claims 17-33 , wherein treating, reducing, or preventing a metabolic disorder is by reducing blood glucose levels of the subject.
35 . The method of any of claims 17-33 , wherein treating, reducing, or preventing a metabolic disorder is by reducing total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c) levels, increasing high-density lipoprotein cholesterol (HDL-c) levels of the subject.
36 . The method of any of claims 17-33 , wherein treating, reducing, or preventing a metabolic disorder is by normalizing liver enzyme levels of the subject.
37 . The method of any of claims 17-33 , wherein treating, reducing, or preventing a metabolic disorder is by altering insulin signaling pathway such that glucose levels are reduced.
38 . The method of any of claims 17-33 , wherein treating, reducing, or preventing a metabolic disorder is by regulating multiple metabolic pathways such as increasing secretion of insulin, improving insulin sensitivity, reducing gluconeogenesis in liver, reducing glucose absorption, ameliorating dyslipidemia, anti-inflammation to achieve the desired pharmacological effects.
39 . A kit comprising: (i) a first agent of berberine or a derivative or analog thereof; (ii) one or more second agent(s) selected from pharmaceutically active organic acids or natural extracts that comprise pharmaceutically active organic acids; (iii) one or more third agent(s) selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium; and (iv) instructions for administering the first agent, the second agent(s) and the third agent(s) to a patient having or at risk of having one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, sarcopenia, muscle atrophy, neurodegenerative diseases, liver diseases, and cancer.
40 . The kit of claim 39 , wherein the one or more second agent(s) are selected from the group consisting of ┐-(+)-α-lipoic acid, hydroxycitric acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, ursolic acid, corosolic acid, cinnamic acid, cholic acid, obeticholic acid, ursodeoxycholic acid, oleanolic acid, salicylic acid, betulinic acid, chlorogenic acid, caffeic acid, bassic acid, acetyl L-carnitine, S-allyl cysteine sulphoxide, S-methyl cysteine sulfoxide, pantothenic acid, ascorbic acid, retinoic acid, rhein, nicotinic acid, biotin, and the others listed in Table 1.
41 . The kit of claim 39 or 40 , wherein the derivative or analog of berberine is selected Table 2.
42 . An acid-base addition salt in substantially pure form, having the formula of:
(
X
+
)
m
(
U
-
)
n
(
I
)
wherein
(a) U − is an anionic moiety of ursodeoxycholic acid or a derivative or analog thereof;
(b) X + is a cationic moiety of a pharmacologically active organic base; and
(c) m and n are integers independently selected from 1, 2, 3, 4, 5 and 6 so as to arrive at a charge neutral salt.
43 . The acid-base addition salt of claim 42 , wherein the derivative or analog of ursodeoxycholic acid is selected from Table 3.
44 . The acid-base addition salt of claim 42 or 43 , wherein the pharmacologically active organic base is selected from the group consisting of berberine, metformin, carnitine, coptisine, palmatine, jatrorrhizine and other organic base that is generally recognized pharmacologically active for one or more diseases or disorders selected from chronic liver diseases, metabolic diseases or disorders, or a related disease or disorder thereof in a mammal, including a human.
45 . The acid-base addition salt of any of claims 42-44 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of berberine or a derivative or analog thereof, and m=1 and n=1.
46 . The acid-base addition salt of claim 45 , wherein the derivative or analog of berberine is selected from Table 2.
47 . The acid-base addition salt of any of claims 42-44 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of metformin or a derivative or analog thereof, and m=1 and n=1.
48 . The acid-base addition salt of claim 47 , wherein the derivative or analog of metformin is selected from Table 4.
49 . The acid-base addition salt of any of claims 42-44 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of carnitine or a derivative or analog thereof, and m=1 and n=1.
50 . The acid-base addition salt of claim 49 , wherein the derivative or analog of carnitine is selected from Table 5.
51 . The acid-base addition salt of any of claims 42-44 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of coptisine or a derivative or analog thereof, and m=1 and n=1.
52 . The acid-base addition salt of any of claims 42-44 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of palmatine or a derivative or analog thereof, and m=1 and n=1.
53 . The acid-base addition salt of any of claims 42-44 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of jatrorrhizine or a derivative or analog thereof, and m=1 and n=1.
54 . A pharmaceutical composition comprising an amount of an acid-base addition salt having the formula of:
(
X
+
)
m
(
U
-
)
n
(
I
)
wherein
(a) U − is an anionic moiety of ursodeoxycholic acid or a derivative or analog thereof;
(b) X + is a cationic moiety of a pharmacologically active organic base; and
(c) m and n are integers independently selected from 1, 2, 3, 4, 5 and 6 so as to arrive at a charge neutral salt,
effective to treat, prevent, or reduce one or more diseases or disorders selected from fatty liver, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), cholestatic liver diseases, graft-versus-host disease of the liver, chronic viral associated liver diseases, alcohol-related liver diseases, metabolic diseases or disorders such as pre-diabetes, diabetes, hyperlipidemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, obesity or a related disease or disorder thereof in a mammal including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
55 . The pharmaceutical composition of claim 54 , wherein the disease or disorder is fatty liver, or NASH or NAFLD.
56 . The pharmaceutical composition of claim 54 , wherein the disease or disorder is cholestatic liver diseases, graft-versus-host disease of the liver, chronic viral associated liver diseases, or alcohol-related liver diseases.
57 . The pharmaceutical composition of claim 54 , wherein the disease or disorder is pre-diabetes, diabetes, hyperlipidemia, diabetic dyslipidemia, or dyslipidemia in statin-intolerant patients.
58 . The pharmaceutical composition of claim 54 , wherein the disease or disorder is obesity.
59 . The pharmaceutical composition of any of claims 54-58 , wherein the derivative or analog of ursodeoxycholic acid is selected from Table 3.
60 . The pharmaceutical composition of any of claims 54-59 , wherein the pharmacologically active organic base is selected from the group consisting of berberine, metformin, carnitine, coptisine, palmatine, jatrorrhizine and other organic base that is generally recognized pharmacologically active for one or more diseases or disorders selected from chronic liver diseases, metabolic diseases or disorders, or a related disease or disorder thereof in a mammal, including a human.
61 . The pharmaceutical composition of any of claims 54-60 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of berberine or a derivative or analog thereof, and m=1 and n=1.
62 . The pharmaceutical composition of claim 61 , wherein the derivative or analog of berberine is selected from Table 2.
63 . The pharmaceutical composition of any of claims 54-60 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of metformin or a derivative or analog thereof, and m=1 and n=1.
64 . The pharmaceutical composition of claim 63 , wherein the derivative or analog of metformin is selected from Table 4.
65 . The pharmaceutical composition of any of claims 54-60 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of carnitine or a derivative or analog thereof, and m=1 and n=1.
66 . The pharmaceutical composition of claim 65 , wherein the derivative or analog of carnitine is selected from Table 5.
67 . The pharmaceutical composition of claim any of claims 54-60 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of coptisine or a derivative or analog thereof, and m=1 and n=1.
68 . The pharmaceutical composition of claim any of claims 54-60 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of palmatine or a derivative or analog thereof, and m=1 and n=1.
69 . The pharmaceutical composition of claim any of claims 54-60 , wherein U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of jatrorrhizine or a derivative or analog thereof, and m=1 and n=1.
70 . The pharmaceutical composition of any of claims 54-69 , further comprising one or more of vitamin E, omega-3 fatty acids, S-adenosylmethionine, N-acetyl cysteine, silymarin, polyenylphosphatidylcholine, resveratrol, and vitamin D.
71 . A method for treating, reducing, or preventing a disease or disorder, comprising
administering to a subject in need thereof a pharmaceutical composition comprising an amount of an acid-base addition salt having the formula of:
(
X
+
)
m
(
U
-
)
n
(
I
)
wherein
(a) U − is an anionic moiety of ursodeoxycholic acid or a derivative or analog thereof;
(b) X + is a cationic moiety of a pharmacologically active organic base; and
(c) m and n are integers independently selected from 1, 2, 3, 4, 5 and 6 so as to arrive at a charge neutral salt,
effective to treat, prevent, or reduce one or more diseases or disorders selected from fatty liver, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), cholestatic liver diseases, graft-versus-host disease of the liver, chronic viral associated liver diseases, alcohol-related liver diseases, metabolic diseases or disorders such as pre-diabetes, diabetes, hyperlipidemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, obesity, or a related disease or disorder thereof in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
72 . The method of claim 71 , wherein the disease or disorder is fatty liver, NAFLD or NASH.
73 . The method of claim 71 , wherein the disease or disorder is cholestatic liver diseases, graft-versus-host disease of the liver, chronic viral associated liver diseases or alcohol-related liver diseases.
74 . The method of claim 71 , wherein the disease or disorder is pre-diabetes, diabetes or hyperlipidemia, diabetic dyslipidemia, or dyslipidemia in statin-intolerant patients.
75 . The method of claim 71 , wherein the disease or disorder is obesity.
76 . The method of any of claims 71-75 , wherein the derivative or analog of ursodeoxycholic acid is selected from Table 3.
77 . The method of any of claims 71-76 , wherein the pharmacologically active organic base is selected from the group consisting of berberine, metformin, carnitine, coptisine, palmatine, jatrorrhizine and other organic base that is generally recognized pharmacologically active for one or more diseases or disorders selected from chronic liver diseases, metabolic diseases or disorders, or a related disease or disorder thereof in a mammal, including a human.
78 . The method of claim 71 or 72 , wherein
U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of berberine or a derivative or analog thereof, and m=1 and n=1, and the subject suffers from NASH.
79 . The method of claim 71 or 72 , wherein
U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of metformin or a derivative or analog thereof, and m=1 and n=1, and the subject suffers from NASH.
80 . The method of claim 71 or 72 , wherein
U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of carnitine or a derivative or analog thereof, and m=1 and n=1, and the subject suffers from NASH.
81 . The method of claim 71 or 72 , wherein
U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of coptisine or a derivative or analog thereof, and m=1 and n=1, and the subject suffers from NASH.
82 . The method of claim 71 or 72 , wherein
U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of palmatine or a derivative or analog thereof, and m=1 and n=1, and the subject suffers from NASH.
83 . The method of claim 71 or 72 , wherein
U − is an anionic moiety of ursodeoxycholic acid, X + is a cationic moiety of jatrorrhizine or a derivative or analog thereof, and m=1 and n=1, and the subject suffers from NASH.
84 . The method of any of claims 71-83 , wherein the pharmaceutical composition further comprises one or more of vitamin E, omega-3 fatty acids, S-adenosylmethionine, N-acetyl cysteine, silymarin, polyenylphosphatidylcholine, resveratrol, and vitamin D.
85 . The method of any of claims 71-83 , wherein the pharmaceutical composition further comprises vitamin E.
86 . The method of any of claims 71-83 , wherein the pharmaceutical composition further comprises omega-3 fatty acids.
87 . The method of any of claims 71-86 , wherein treating, reducing, or preventing a disease or disorder is by normalizing liver enzyme levels of the subject.
88 . An acid-base addition salt in substantially pure form, having the formula of:
(
B
+
)
m
(
Y
-
)
n
(
II
)
wherein
(a) B + is a cationic moiety of berberine or a derivative or analog thereof;
(b) Y − is an anionic moiety of a pharmacologically active organic acid; and
(c) m and n are integers independently selected from 1, 2, 3, 4, 5 and 6 so as to arrive at a charge neutral salt.
89 . The acid-base addition salt of claim 88 , wherein the berberine derivative or analog is selected from Table 2.
90 . The acid-base addition salt of claim 88 or 89 , wherein the pharmacologically active organic acid is selected from the group consisting of ┐-(+)-α-lipoic acid, hydroxycitric acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), ursolic acid, and corosolic acid, cinnamic acid, cholic acid, obeticholic acid, ursodeoxycholic acid, oleanolic acid, salicylic acid, betulinic acid, chlorogenic acid, caffeic acid, bassic acid, acetyl L-carnitine, S-allyl cysteine sulphoxide, S-methyl cysteine sulfoxide, pantothenic acid, ascorbic acid, retinoic acid, nicotinic acid, biotin and other organic acid that is generally recognized pharmacologically active for one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, neurodegenerative diseases, liver diseases, sarcopenia, muscle atrophy, inflammation, and cancer, or a related disease or disorder thereof in a mammal, including a human by those of skill in the art.
91 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of ┐-(+)-┐-Lipoic acid, and m=1 and n=1.
92 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of hydroxycitric acid, and m=1 and n=1, or m=2 and n=1, or m=3 and n=1.
93 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of EPA, and m=1 and n=1.
94 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of DHA, and m=1 and n=1.
95 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of DPA, and m=1 and n=1.
96 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of ursolic acid, and m=1 and n=1.
97 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of corosolic acid, and m=1 and n=1.
98 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of cholic acid, and m=1 and n=1.
99 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of obeticholic acid, and m=1 and n=1.
100 . The acid-base addition salt of claim 88 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of ursodeoxycholic acid, and m=1 and n=1.
101 . A pharmaceutical composition comprising an amount of an acid-base addition salt having the formula of:
(
B
+
)
m
(
Y
-
)
n
(
II
)
wherein
(a) B + is a cationic moiety of berberine or a derivative or analog thereof;
(b) Y − is an anionic moiety of a pharmacologically active organic acid; and
(c) m and n are integers independently selected from 1, 2, 3, 4, 5 and 6 so as to arrive at a charge neutral salt,
effective to treat, prevent, or reduce one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, neurodegenerative diseases, liver diseases, sarcopenia, muscle atrophy, inflammation, and cancer, or a related disease or disorder thereof in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
102 . The pharmaceutical composition of claim 101 , wherein the disease or disorder is a metabolic disorder is selected from diabetes, diabetic complications, dyslipidemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, obesity, metabolic syndromes, pre-diabetes, fatty liver, NAFLD and NASH.
103 . The pharmaceutical composition of claim 102 , wherein the metabolic disorder is type 1 or type 2 diabetes.
104 . The pharmaceutical composition of claim 101 , wherein the disease or disorder is atherosclerosis.
105 . The pharmaceutical composition of claim 101 , wherein the disease or disorder is heart diseases.
106 . The pharmaceutical composition of claim 101 , wherein the disease or disorder is neurodegenerative diseases.
107 . The pharmaceutical composition of claim 101 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease.
108 . The pharmaceutical composition of claim 101 , wherein the disease or disorder is cancer.
109 . The pharmaceutical composition of claim 108 , wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, lung cancer, hepatocellular carcinoma, pancreatic cancer, gastric carcinoma, colorectal cancer, leukemia, multiple myeloma, melanoma and glioblastoma.
110 . The pharmaceutical composition of claim 101 , wherein the disease or disorder is sarcopenia, or muscle atrophy.
111 . The pharmaceutical composition of claim 110 , wherein the muscle atrophy is skeletal muscle atrophy.
112 . The pharmaceutical composition of any of claims 101-111 , wherein the berberine derivative or analog is selected from Table 2.
113 . The pharmaceutical composition of any of claims 101-112 , wherein the pharmacologically active organic acid is selected from the group consisting of ┐-(+)-α-lipoic acid, hydroxycitric acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, ursolic acid, and corosolic acid, cinnamic acid, cholic acid, obeticholic acid, ursodeoxycholic acid, oleanolic acid, salicylic acid, betulinic acid, chlorogenic acid, caffeic acid, bassic acid, acetyl L-carnitine, S-allyl cysteine sulphoxide, S-methyl cysteine sulfoxide, pantothenic acid, ascorbic acid, retinoic acid, nicotinic acid, biotin and other organic acid that is generally recognized pharmacologically active for one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, neurodegenerative diseases, liver diseases, sarcopenia, muscle atrophy, inflammation, and cancer, or a related disease or disorder thereof in a mammal, including a human by those of skill in the art.
114 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of ┐-(+)-┐-Lipoic acid, and m=1 and n=1.
115 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of hydroxycitric acid, and m=1 and n=1, or m=2 and n=1, or m=3 and n=1.
116 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of EPA, and m=1 and n=1.
117 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of DHA, and m=1 and n=1.
118 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of DPA, and m=1 and n=1.
119 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of ursolic acid, and m=1 and n=1.
120 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of corosolic acid, and m=1 and n=1.
121 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of cholic acid, and m=1 and n=1.
122 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of obeticholic acid, and m=1 and n=1.
123 . The pharmaceutical composition of claim 101 , wherein B + is a cationic moiety of berberine, Y − is an anionic moiety of ursodeoxycholic acid, and m=1 and n=1.
124 . The pharmaceutical composition of any of claims 101-123 , further comprising vitamin D.
125 . A method for treating, reducing, or preventing a disease or disorder, comprising
administering to a subject in need thereof a pharmaceutical composition comprising an amount of an acid-base addition salt having the formula of:
(
B
+
)
m
(
Y
-
)
n
(
II
)
wherein
(a) B + is a cationic moiety of berberine or a derivative or analog thereof;
(b) X − is an anionic moiety of a pharmacologically active organic acid; and
(c) m and n are integers independently selected from 1, 2, 3, 4, 5 and 6 so as to arrive at a charge neutral salt,
effective to treat, prevent, or reduce one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, neurodegenerative diseases, liver diseases, sarcopenia, muscle atrophy, inflammation, and cancer, or a related disease or disorder thereof in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
126 . The method of claim 125 , wherein the metabolic disorder is selected from diabetes, diabetic complications, dyslipidemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, obesity, metabolic syndromes, pre-diabetes, fatty liver, NAFLD and NASH.
127 . The method of claim 125 or 126 , wherein the metabolic disorder is type 1 or type 2 diabetes.
128 . The method of claim 125 , wherein the disorder is atherosclerosis.
129 . The method of claim 125 , wherein the disorder is heart diseases.
130 . The method of claim 125 , wherein the disorder is neurodegenerative diseases.
131 . The method of any of claims 125-130 , wherein the berberine derivative or analog is selected from Table 2.
132 . The method of any of claims 125-131 , wherein the pharmacologically active organic acid is selected from the group consisting of ┐-(+)-α-lipoic acid, hydroxycitric acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, ursolic acid, and corosolic acid, cinnamic acid, cholic acid, obeticholic acid, ursodeoxycholic acid, oleanolic acid, salicylic acid, betulinic acid, chlorogenic acid, caffeic acid, bassic acid, acetyl L-carnitine, S-allyl cysteine sulphoxide, S-methyl cysteine sulfoxide, pantothenic acid, ascorbic acid, retinoic acid, nicotinic acid, biotin and other organic acid that is generally recognized pharmacologically active for one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, neurodegenerative diseases, liver diseases, sarcopenia, muscle atrophy, inflammation, and cancer, or a related disease or disorder thereof in a mammal, including a human by those of skill in the art.
133 . The method of any of claims 125-127 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of ┐-(+)-┐-lipoic acid, and m=1 and n=1, and the subject suffers from diabetes and diabetic complications.
134 . The method of any of claims 125-127 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of hydroxycitric acid, and m=1 and n=1, or m=2 and n=1, or m=3 and n=1 and the subject suffers from diabetes and obesity.
135 . The method of claim any of claims 125-127 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of EPA, and m=1 and n=1, and the subject suffers from diabetes and dyslipidemia or hyperlipidemia (hypercholesterolemia, hypertriglyceridemia).
136 . The method of claim any of claims 125-129 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of EPA, and m=1 and n=1, and the subject suffers from a heart disease.
137 . The method of claim any of claims 136 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of EPA, and m=1 and n=1, and the subject suffers from atherosclerosis.
138 . The method of any of claims 125-127 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of DHA, and m=1 and n=1, and the subject suffers from diabetes and dyslipidemia or hyperlipidemia (hypercholesterolemia, hypertriglyceridemia).
139 . The method of any of claims 125-129 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of DHA, and m=1 and n=1, and the subject suffers from a heart disease.
140 . The method of claim any of claims 139 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of DHA, and m=1 and n=1, and the subject suffers from atherosclerosis.
141 . The method of claim any of claims 125-127 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of DPA, and m=1 and n=1, and the subject suffers from diabetes and dyslipidemia or hyperlipidemia (hypercholesterolemia, hypertriglyceridemia).
142 . The method of claim any of claims 125-129 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of DPA, and m=1 and n=1, and the subject suffers from a heart disease.
143 . The method of claim any of claims 142 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of DPA, and m=1 and n=1, and the subject suffers from atherosclerosis.
144 . The method of any of claims 125-127 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of ursolic acid, and m=1 and n=1, and the subject suffers from diabetes and muscle atrophy.
145 . The method of any of claims 125-127 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of corosolic acid, and m=1 and n=1, and the subject suffers from diabetes and muscle atrophy.
146 . The method claim 125 or 126 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of cholic acid, and m=1 and n=1, and the subject suffers from dyslipidemia, fatty liver, NAFLD or NASH.
147 . The method claim 125 or 126 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of obeticholic acid, and m=1 and n=1, and the subject suffers from dyslipidemia, fatty liver, NAFLD or NASH.
148 . The method of claim 125 or 126 , wherein
B + is a cationic moiety of berberine, Y − is an anionic moiety of ursodeoxycholic acid, and m=1 and n=1, and the subject suffers from dyslipidemia, fatty liver, NAFLD or NASH.
149 . The method of any of claims 125-148 , wherein the pharmaceutical composition further comprises vitamin D.
150 . The method of any of claims 125-149 , wherein treating, reducing, or preventing a metabolic disorder is by reducing glucose levels of the subject.
151 . The method of any of claims 125-149 , wherein treating, reducing, or preventing a metabolic disorder is by reducing total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c) levels, increasing high-density lipoprotein cholesterol (HDL-c) levels of the subject.
152 . The method of any of claims 125-149 , wherein treating, reducing, or preventing a metabolic disorder is by normalizing liver enzyme levels of the subject.
153 . The method of any of claims 125-149 , wherein treating, reducing, or preventing a metabolic disorder is by altering insulin signaling pathway such that glucose levels are reduced.
154 . The method of any of claims 125-149 , wherein treating, reducing, or preventing a metabolic disorder is by regulating multiple metabolic pathways such as increasing secretion of insulin, improving insulin sensitivity, reducing gluconeogenesis in liver, normalizing lipid levels in liver, reducing glucose absorption, ameliorating dyslipidemia, anti-inflammation to achieve the desired pharmacological effects.Join the waitlist — get patent alerts
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